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In a Cornish village in August 1860, the inhabitants of the town are dying from a mysterious plague that seems to be spreading at an accelerated rate. Even the local doctor, Peter Tompson (Brook Williams), cannot combat the disease. Alarmed, Tompson sends for outside help from his friend Sir James Forbes (André Morell). Accompanying Sir James is his daughter Sylvia (Diane Clare). In an attempt to learn more about the disease, Sir James and Dr. Thompson disinter the corpses that were recently buried. To their surprise, the men find all the coffins empty. Conducting further investigations on the mystery lead the doctors to encounter zombies walking near an old, deserted tin mine on the estate of Squire Clive Hamilton (John Carson). Sir James is informed that the squire lived in Haiti for several years and practiced voodoo rituals, as well as black magic. This information leads him to research on the subject of the black arts.

Later that evening, Squire Hamilton pays Sylvia a visit. Purposely, Hamilton manages to shatter a wine glass, and Sylvia happens to cut her finger on one of the sharp edges of the glass. Secretly, the Squire conceals a piece of the blood-stained glass into his coat pocket and departs. With a vestige of Sylvia's blood, Hamilton uses his voodoo magic to lure the heroine into venturing in the dark woods. She is led to the abandoned tin mine by an army of walking zombies for a voodoo ceremony that will transform her into one of the walking dead.

While Tompson follows Sylvia to the mines, Sir James investigates the Squire's house and finds some small figures in coffins the Squire uses for his voodoo. After a struggle with one of the Squire's henchmen the room is accidentally set ablaze, Sir James barely managing to escape after threatening a servant who notices the inferno for information on the mine. He races to the mines to join Tompson, while in the mansion the figures in the coffins catch fire, causing their zombie counterparts to do the same and go crazy. Using the distraction caused by the burning crazed zombies Sir James and the doctor rescue Sylvia and flee from the burning flames as they listen to the anguished screams of Hamilton and his zombies; thus the plague is ended.

Production on the film began on 28 July 1965 at Bray Studios. It was shot back-to-back with The Reptile using the same sets, a Cornish village created on the backlot by Bernard Robinson.[2] Pearce and Ripper appeared in both films.

The Plague of the Zombies has been well received by critics. AllMovie called it a "spooky, atmospheric horror opus that ranks among Hammer Films' finest."[3]Time Out London wrote, "perhaps a little tame these days, compared with modern gore-shock, but Gilling's Hammer chiller [...] is highly atmospheric."[4]Variety wrote that it is a well-made horror film with formulaic scripting.[5]The Hammer Story: The Authorised History of Hammer Films wrote, "much has been said of The Plague of the Zombies' influence on genre landmark Night of the Living Dead, made in 1968. A unique and shocking experiment in pushing the parameters of Hammer horror, The Plague of the Zombies deserves greater recognition in its own right."[6] Writing in The Zombie Movie Encyclopedia, academic Peter Dendle called it a "well-acted and capably-produced" zombie film that would go on to influence the depiction of zombies in many other films.[7]

The film was adapted into a 13-page comic strip for the October 1977 issue of the magazine House of Hammer (volume 1, # 13, published by Top Sellers Limited). It was drawn by Trevor Goring and Brian Bolland from a script by Steve Moore. The cover of the issue featured a painting by Brian Lewis of a famous scene from the film.[10]